Therapieoptionen und outcome bei idiopathischen entzündlichen Muskelerkrankungen

Zusammenfassung

Die idiopathischen entzündlichen Muskelerkrankungen (IIM) sind eine sehr heterogene Gruppe, die sich immer besser differenzieren lässt. Damit eröffnen sich mehr Möglichkeiten für gezieltere Therapien, die zum einen auf die Veränderung pathogenetischer Faktoren gerichtet sind. Zum anderen sollen sie Krankheitsaktivität vermindern, Muskelaufbau fördern, Organschäden verhindern und Lebensqualität verbessern.

Die folgende Übersichtsarbeit fasst die vorhandenen Daten zu bereits angewandten Behandlungen in der Praxis zusammen und gibt einen Ausblick auf zukünftige Alternativen.

Für die Polymyositis (PM) und Dermatomyositis (DM) sind Glukokortikoide weiter unverzichtbarer Therapiebestandteil. Eine frühe Kombination mit konventionellen DMARDs hat sich durchgesetzt. Die ProDerm- Studie stellt für die Immunglobulintherapie in der Praxis eine gute Basis dar. Rituximab (RTX) löst Cyclophosphamid (CYC) bei schweren Verlaufsformen immer mehr ab.

Für Abatacept, Jak-Kinase-Hemmer, Apremilast, Sifalimumab und Lenabasum müssen vielversprechende erste Ergebnisse durch weiter Studien untermauert werden. Anspruchsvoll ist die Behandlung bei extramuskulärer Beteiligung. Von großem Interesse ist der zukünftige Stellenwert von Nintedanib bei der interstitiellen Lungenerkrankung im Rahmen einer Myositis (IIM-ILD).

Die Therapie der Einschlusskörperchen- Myositis (IBM) ist immer noch eine große Herausforderung. Zahlreiche Studien haben bisher nicht überzeugend zu einer Besserung der Prognose führen können. Spätestens bei therapierefraktärem Verlauf sollte an eine Malignom- assoziierte Myositis gedacht werden. Gelegentlich verbirgt sich auch eine hereditäre Myopathie hinter einer, zum Beispiel durch einen Infekt oder Überlastung getriggerten, Myositis.

Komplikationen im Verlauf, wie Dysphagie, Infektionen, Myokardbeteiligung stellen keine Seltenheit dar. Häufig besteht Multimorbidität. Eine interdisziplinäre Zusammenarbeit in einem kompetenten Team, in dem erfahrene Physio-, Ergo- und Psychotherapeuten fester Bestandteil sind, ist unabdingbar für eine erfolgreiche Begleitung dieser Patienten.

Abstract

Idiopathic inflammatory myopathies (IIM) are a very heterogeneous group of conditions, which can now be increasingly differentiated. This paves the way for targeted treatment. Therapies aim to change pathogenic mechanisms and are focused on reducing disease activity, encouraging muscle development, preventing organ damage, and improving quality of life.

The following review summarises existing data on the treatments currently used and provides an overview of future alternatives. Glucocorticoids continue to be an indispensable component of the treatment of polymyositis (PM) and dermatomyositis (DM).

A combination of drugs including conventional DMARDs has long been established. The ProDERM study provides a solid basis for the use of immunoglobulins in the clinical setting. In severe forms of the disease, rituximab is increasingly replacing cyclophosphamide. Promising early results obtained with abatacept, janus kinase-inhibitors, apremilast, sifalimumab and lenabasum must be corroborated by further studies. The treatment of extramuscular involvement is a challenging issue. The future value of nintedanib in the treatment of interstitial lung disease associated with myositis (IIM-ILD) is of significant interest. The management of inclusion body myositis (IBM) continues to be a major challenge. A number of studies conducted thus far have yielded no convincing evidence of any improvement in the prognosis of the disease. When a patient shows signs of treatment-refractory disease, it is high time for a clinician to consider cancer-associated myositis. In some cases, a hereditary myopathy may be hidden behind myositis triggered by infection or overexertion.

Complications in the course of disease, such as dysphagia, infection or myocardial involvement, are not rare at all. Multimorbidity is quite common. Interdisciplinary cooperation is an absolute prerequisite for supporting and accompanying a patient successfully. A competent interdisciplinary team must include an experienced physiotherapist, an occupational therapist and a psychotherapist.

Schlüsselwörter

idiopathischen entzündlichen Muskelerkrankungen - Studienlage - Therapiestandards

Key words

inflammatory idiopathic myositis - standard of care - treatment-refractory disease

Publication History

Article published online:
24 August 2021

• Literatur

• 1 Martinez M, Zampieri S, Franco C. et al. Nonimmune mechanisms in idiopathic inflammatory myopathies. Curr Opin Rheumatol 2020; 32: 515-522
• 2 Rider L, Werth V, Huber A. et al. Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent global activity, Manual Muscle Testing (MMT) Health Assessment Questionnaire (HAQ). Arthritis Care Res (Hoboken) 63: 118-157
• 3 Aggarwal R, Rider LG, Ruperto N. et al. International Myositis Assessment and Clinical Studies Group and the Paedriatric Rheumatology International Trials Organisation. 2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis 2017; 76: 792-801
• 4 Gordon P, Winer J, Hoogendijk E. et al. Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis (Review). Cochrane Database of Systematic Reviews 2012; issue 8. Art. No CD003643
• 5 Kohsaka H, Mimori T, Kanda T. et al. Treatment consensus for management of polymyositis and dermatomyositis among rheumatologists, neurologists and dermatologists. Neurology and Clinical Neuroscience 2019; 3-21
• 6 Nzeusseu A, Brion F, Lefèbvre C. et al. Functional outcome of myositis patients: can a low-dose glucokorticoid regimen achieve good functional results?. Clin. Exp. Rheumatol. 1999; 17: 441-446
• 7 Van de Vlekkert J, Hoogendijk J, de Haan R. et al. Oral dexamethasone pulse therapy versus daily prednisolone in subacute onset myositis, a randomised clinical trial. Neuromuscul. Disord. 2010; 20: 382-389
• 8 Vencovsky J, Jarosova K, Machacek S. et al. Cyclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis. Scand J Rheumatol 2000; 29: 95-102
• 9 Keyßer G, Zierz S, Kornhuber M. Treatment of adult idiopathic inflammatory myopathies with conventional immunosuppressive drugs: results of a retrospective study. Z Rheumatol 2019; 78: 183-189
• 10 Rouster-Stevens K, Morgan G, Wang D. et al. Mycophenolate mofetil: a possible therapeutic agent for children with juvenile dermatomyositis. Arthritis Care Res (Hoboken) 2010; 62: 1446-1451
• 11 Hanaoka H, Ilda H, Kiyokawa T. et al. Mycophenolate mofetil treatment with or without a calcineurin inhibitor in resistant inflammatory myopathy. Clin Rheumatol 2019; 38: 585-590
• 12 Ge Y, Zhou H, Shi J. et al. The efficacy of tacrolimus in patients with refractory dermatomyositis/polymyositis: a systemic review. Clin Rheumatol 2015; 34: 2097-2103
• 13 Ueno K, Shimojima Y, Kishida D. et al. Advantage of administering tacrolimus for improving prognosis of patients with polymyositis and dermatomyositis. Int J Rheum Dis 2016; 19: 1322-1330
• 14 Riley P, Maillard S, Wedderburn L. et al. Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety. Rheumatology (Oxford) 2004; 43: 491-496
• 15 Nagappa M, Taly A, Sinha S. et al. Efficacy and limitation of pulse cyclophosphamide therapy in polymyositis and dermatomyositis. J Clin Neuromusc Dis 2013; 14: 161-168
• 16 Dalakas M, Illa I, Dambrosia J. et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993; 329: 1993-2000
• 17 Miyasaka N, Hara M, Koike T. et al. Effects of intravenous immunoglobin therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double-blind placebo-controlled trial. Mod. Rheumatol. 2012; 22: 382-393
• 18 Cherin P, Pelletier S, Teixeira A. et al. Results and longterm follow up of intravenous immunglobulin infusions in chronic, refractory polymyositis: an open study with thirtyfive adult patients. Arthritis Rheum 2002; 46: 467-474
• 19 Danieli M, Malcangi G, Palmieri C. et al. Cyclosporin A and intravenous immunglobulin treatment in polymyositis/dermatomyositis. Ann. Rheum. Dis 2002; 61: 37-41
• 20 Danieli M, Calcabrini L, Calabrese V. et al. Intravenous immunoglobulin as add on treatment with mycophenolate mofetil in severe myositis. Autoimmun.Rev. 2009; 9: 124-127
• 21 Aggarwal R, Charles-Schoeman C, Schesssl J. et al. Prospective, double-blind, randomized, placebo-controlled phase III study evaluating efficacy and safety of octagam 10% in patients with dermatomyositis („ProDerm Study“). Medicine (Balitmore) 08..2012; 100: e23677 doi: 10.1097/MD.0000000000023677
• 22 Chung L, Genovese M, Fiorentino D. A pilot trial of rituximab in the treatment of patients with dermatomyositis. Arch Dermatol 2007; 143: 763-767
• 23 Unger L, Kampf S, Lüthke K. et al. Rituximab therapy in patients with refractory dermatomyositis or polymyositis: differential effects in a real-life population. Rheumatology (Oxford) 2014; 53: 1630-1638
• 24 Mok C, Ho L, To C. Rituximab for refractory polymyositis: an open- label prospective study. J Rheumatol 2007; 34: 1864-1868
• 25 Oddis C, Reed A, Aggarwal R. et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: A randomized, placebo-phase trial. Arthritis Rheum 2013; 65: 314-324
• 26 Aggarwal R, Bandos A, Reed A. et al. Predictors of clinical improvement in rituximab-treated refractory adult and juvenile dermatomyositis and adult polymyositis. Arthritis Rheumatol 2014; 66: 740-749
• 27 Aggarwal R, Oddis C, Goudeau D. et al. Autoantibody levels in myositis patients correlate with clinical response during B cell depletion with rituximab. Rheumatology (Oxford) 2016; 55: 1710
• 28 Leclair V, Galindo-Feria A, Dastmalchi M. et al. Efficacy and safety of rituximab in anti-synthetase antibody positive and negative subjects with idiopathic inflammatory myopathy: a registry-based study. Rheumatology (Oxford) 2019; 58: 1214-1220
• 29 Aggarwal R, Loganathan P, Koontz D. et al. Cutaneous improvement in refractory adult and juvenile dermatomyositis after treatment with rituximab. Rheumatology 2016; 56: 247-254
• 30 De Souza F, Miossi R, de Moraes J. et al. Favorable rituximab response in patients with redractory idiopathic inflammatory myopathies. Advances in Rheumatology 2018; 58: 31
• 31 Saunders P, Tsipouri V, Keir G. et al. Rituximab versus cyclphosphamide fort he treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial. Trials 2017; 18: 275
• 32 Musuruana J, Cavallasca J. Abatacept for treatment of refractory polymyositis. Joint Bone Spine 2011; 78: 431-432
• 33 Arabshahi B, Silvermann R, Jones O. et al. Abatacept and sodium thiosulfate for treatment of recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis. J Pediatr 2012; 160: 520-522
• 34 Kerola A, Kauppi M. Abatacept as asuccesfull therapy for myositis- a case based review. Clin Rheumatol 2015; 34: 609-612
• 35 Tjärnlund A, Tang Q, Wick C. et al. Abatacept in the treatment of adult dermatomyositis and polymyositis: A randomised, phase IIb treatment delayed-start trial. Ann Rheum Dis 2018; 77: 55-62
• 36 Tang Q, Ramsköld D, Krystufkova O. et al. Effect of CTLA4-Ig (abatacept) treatment on T-cells and B cells in peripheral blood of patients with polymyositis and dermatomyositis. Scand J Immunol 2019; 89: e12732
• 37 Moghadam-Kia S, Charlton D, Aggarwal R. et al. Management of refractory cutaneous dermatomyositis: potential role of Janus kinase inhibition with tofacitinib. Rheumatology (Oxford) 2019; 58: 1011-1015
• 38 Paik JJ, Casciola-Rosen L, Shin JY. et al. Arthritis Rheumatol. 2020; Dec 1 doi:10.1002/art.41602 Online ahead of print
• 39 Efthimiou P, Schwartzman S, Kagen L. Possible role for tumour necrosis factor inhibitors in the treatment of resistant dermatomyositis and polymyositis: a retrosspective study of eight patients. Ann Rheum Dis 2006; 65: 1233-1236
• 40 Uthman I, El-Sayad J. Refractory polymyositis responding to infliximab. Rheumatology. 2004; 43: 1198-1199
• 41 Hengstman G, van den Hoogen F, van Engelen B. Treatment of dermatomyositis and polymyositis with anti-tumor necrosis factor-alpha: long-term follow-up. Eur Neurol 2004; 52: 61-63
• 42 Labioche I, Liozon E, Weschler B. et al. Refractory polymyositis responding to infliximab: extended follow-up. Rheumatology. 2004; 43: 531-532
• 43 Muscle Study Group A randomized, pilot trial of etanercept in dermatomyositis. Ann Neurol 2011; 70: 427-436
• 44 Hengstman G, De Bleecker J, Feist E. et al. Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate. Eur Neurol 2008; 59: 159-163
• 45 Dastmalchi M, Grundtman C, Alexanderson H. et al. A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis 2008; 67: 1670-1677
• 46 Schiffenbauer A, Garg M, Castro C. et al. A randomized, double-blind, placebo-controlled trial of infliximab in refractory polymyositis and dermatomyositis. Semin Arthritis Rheum 2018; 47: 858-864
• 47 Brunasso A, Aberer W, Massone C. New onset of dermatomyositis/polymyositis during anti- TNF-a therapies: a systematic literature review. ScientificWorldJournal. 29.01.2014; 2014: 179180 doi: 10.1155/2014/179180
• 48 Zong M, Dorph C, Dastmalchi M. et al. Anakinra treatment in patients with refractory inflammatory myopathies and possible predictive response biomarkers: a mechanistic study with 12 months follow-up. Ann Rheum Dis 2014; 73: 913-920
• 49 Groh M, Rogowska K, Monsarrat O. et al. Interleukin-1 receptor antagonist for refractory anti-MDA5 clinically amyopathic dermatomyopathy. Clin Exp Rheumatol 2015; 33: 904-905
• 50 Bitar C, Maghfour J, Ho-Pham H. et al. Apremilast as a potential treatment for moderate to severe dermatomyositis: a retrospective study of 3 patients. JAAD Case Reports 2019; 5: 191-194
• 51 Higgs B, Zhu W, Morehouse C. et al. A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients. Ann Rheum Dis 2014; 73: 256-262
• 52 Guo X, Higgs B, Rebelatto M. et al. Supression of soluble T cell-associated proteins by an interferon- α monoclonal antibody in adult patients with dermatomyositis or polymyositis. Rheumatology. 2013; 53: 686-695
• 53 Huard C, Gullà S, Bennett D. et al. Correlation of cutaneous disease activity with type I interferon gene signature and interferon ß in dermatomyositis. Br J Dermatol 2017; 176: 1224-1230
• 54 Werth V, Hajazi E, Pena S. et al. A Phase 2 Study of Safety and Efficacy of Anabasum (JBT-101), a Cannabinoid Receptor Type 2 Agonist, in Refractory Skin-Predominant Dermatomyositis (abstract). Arthritis Rheumatol 2017; 69
• 55 Narazaki M, Hagihara K, Shima Y. et al. Therapeutic effect of tocilizumab on two patients with polymyositis. Rheumatology (Oxford) 2011; 50: 1344-1346
• 56 Aggarwal R, Rockette H, Venturupalli S. et al. Tocilizumab in Myositis: Results of a Phase IIb Double-Blind Randomized Controlled Trial [abstract 0958]. Arthritis Rheumatol 2020; 72
• 57 Mimori T, Nakashima R, Hosono Y. Interstitial lung disease in myositis: clinical subsets, biomarkers, and treatment. Curr Rheumatol. Rep. 2012; 14: 264-274
• 58 Ye S, Chen XX, Lu X. et al. Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: a retrospective cohort study. Clin Rheumatol 2007; 26: 1647-1654
• 59 Kurasawa K, Arai S, Namiki Y. et al. Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis. Rheumatology (Oxford) 2018; 57: 2114-2119
• 60 Yokoyama Y, Furuta S, Ikeda K. et al. Corticosteroid-sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis. Mod Rheumatol 2015; 25: 888-892
• 61 Suzuka T, Kotani T, Takeuchi T. et al. Efficacy and safety of oral high-trough level tacrolimus in acute/subacute interstitial pneumonia with dermatomyositis. Int J Rheum Dis 2019; 22: 303-313
• 62 Huapaya JA, Silhan L, Pinal-Fernandez I. et al. Long-term treatment with azathioprine and mycophenolate mofetil for myositis-related interstitial lung disease. Chest 2019; 156: 896-906
• 63 Tsuji H, Nakashima R, Hosono Y. et al. Multicenter prospective study of the efficacy and safety of combined immunosuppressive therapy with high-dose glucocorticoid, tacrolimus, and cyclophosphamide in interstitial lung diseases accompanied by anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Arthritis Rheumatol 2020; 72: 488-498
• 64 Chen Z, Wang X, Ye S. Tofacitinib in Amyopathic Dermatomyositis-Associated Interstitial Lung Disease. N Engl J Med 2019; 381: 291-293
• 65 Distler O, Kristin B, Highland M. et al. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med 2019; 380: 2518-2528
• 66 Liang J, Cao H, Yang Y. et al. Efficacy and Tolerability of Nintedanib in Idiopathic-Inflammatory-Myopathy-Related Interstitial Lung Disease: A Pilot Study. 2021; Front.Med 8: 626953 doi:10.3389/fmed.2021.626953
• 67 Kosmidis M, Pikazis D, Vlachoyiannopoulos P. et al. Trial of canakinumab, an IL-1beta receptor antagonist, in patients with inclusion body myositis. Neurol Neuroimmunol Neuroinflamm 2019; 6: e581
• 68 Dalakas M, Rakocevic G, Schmidt J. et al. Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis. Brain 2009; 132: 1536-1544
• 69 Benveniste O, Hogrel J, Belin L. et al. Sirolimus for treatment of patients with inclusion body myositis: a ranomized, double-blind, placebo-controlled, proof-of-concept, phase 2b trial. Lancet Rheumatol 2021; 3: e40-e48
• 70 Machado P, Miller A, Herbelin L. et al. Safety and tolerability of arimoclomol in patients with sporadic inclusion body myositis: a randomised, double-blind, placebo-controlled, phase IIa proof-of-concept trial. Ann Rheum Dis 2013; 72: 164
• 71 Ahmed M, Machado P, Miller A. et al. Targeting protein homeostasis in sporadic inclusion body myositis. Sci Transl Med 2016; 8: 331ra41
• 72 Amato A, Sivakumar K, Goyal N. et al. Treatment of sporadic inclusion myositis with biagrumab. Neurology 2014; 83: 2239-2246
• 73 Hanna M, Badrising U, Benveniste O. et al. Safety and efficacy of intravenous bimagrumab in inclusion body Myositis (RESILENT): a randomized, double-blind, placebo-controlled Phase 2b trial. Lancet Neurol 2019; 18: 834-844
• 74 Mendell J, Sahenk Z, Al-Zaidy S. et al. Follistatin gene therapy for sporadic inclusion body myositis improves functional outcomes. Mol Ther 2017; 25: 870-879
• 75 Rutkove S, Parker R, Nardin R. et al. A pilot randomized trial of oxandrolone in inclusion body myositis. Neurology 2002; 58: 1081-1087
• 76 Snedden A, Lilleker J, Chinoy H. In Pursuit of an Effective Treatment: the Past, Present and Future of Clinical Trials in Inclusion Body myositis. Curr Treat Options in Rheum. 2021; DOI 10.1007/s40674-020-00169-4
• 77 De Souza J, Hoff L, Shinjo G. Intravenous human immunglobulin and/or methylprednisolone pulse therapies as a possible treat- to- traget strategy in immune-mediated necrotizing myopathies. Rheumatol Int 2019; 39: 1201-1212
• 78 Feng F, Li Y. J S. et al. Tacrolimus combined with corticosteroids effectively improved the outcome of a cohort of patients with immune-mediated necrotising myopathy. Clin Exp Rheumatol 2019; 37: 740-747
• 79 Nissen S, Stroes E, Dent-Acosta R. et al. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Trial. JAMA 2016; 315: 1580-1590
• 80 Landon-Cardinal O, Allenbach Y, Soulages A. et al. Rituximab in the treatment of refractory anti-HMGCR immunemediated necrotizing myopathy. J Rheumatol 2019; 46: 623-627
• 81 Wallace A, Pietrusz A, Dewar E. et al. Community exercise is feasible for neuromuscular diseases and can improve aerobic capacity. Neurology 2019; 92: e1773-e1785
• 82 Oddis C, Aggarwal R. Treatment in myositis. Nat Rev Rheumatol 2018; 14: 279-289
• 83 De Souza J, De Oliviera D, Perin l. et al. Feasibility, safety and efficacy of exercise training in immune-mediated necrotising myopathies: a quasi-experimental prospective study. Clin Exp Rheumatol 2019; 37: 235-241
• 84 Alemo M, Dastmalchi M, Katz A. et a. Improved exercise performance and increased aerobic capacity after endurance training of patients with stable Polymyositis and dermatomyositis. Arthritis Res Ther 2013; 15: R83
• 85 Lundberg I, Venovsky J, Alexanderson H. Therapy of myositis:biological and physical. Curr Opin Rheumatol 2014; 26: 704-711
• 86 Tiffreau V, Rannou F, Kopciuch F. et al. Postrehabilitation Functional Improvements in Patients With Inflammatory Myopathies: The Results of a Randomized Controlled Trial. Arch Phys Med Rehabil 2017; 98: 227-234
• 87 Askari A, Vignos P, Moskowitz R. Steroid myopathy in connective tissue disease. Am. J. Med. 1976; 61: 485-492